Our long-term goal is to understand how cardiovascular tissues are targeted for attack in the context of systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In this proposal we focus on macrophages, a key inflammatory cell type. Although the presence of macrophages in inflamed cardiovascular tissues in patients with these diseases has long been recognized, the tools to dissect their precise role in disease pathogenesis have only recently been developed. We propose to employ these powerful new tools to study how macrophages contribute to cardiovascular inflammation in the setting of systemic rheumatic diseases. We have recently described the occurrence of cardiac valve inflammation in a mouse model of autoimmune arthritis. Valvular carditis in this model is similar to that seen in rheumatic diseases in humans. The cytokine interleukin-17 (IL-17) and immune complexes interacting with activating Fc receptors are critical for carditis to develop. Importantly, macrophages are the predominant inflammatory cell type in this model. Macrophages are characterized broadly as M1 (classical/pro-inflammatory) or M2 (alternative/anti-inflammatory). Our preliminary data suggest that both of these populations may contribute to valvular carditis. We propose to study essential aspects of macrophage biology in this model system: entry into the cardiovascular tissue, activation, and effector function. First, we will determine how macrophages enter the cardiac valves, focusing on the cell surface receptor VLA-4. Next, we will explore how IL-17, activating Fc receptors and TLR4 drive macrophage activation toward M1 or M2 phenotypes. We will then dissect the relative contributions of the M1 and M2 macrophage populations to disease severity, by interfering with the differentiation of these cell subsets or with their key molecular products. Using recently-developed conditional gene knockout animals in conjunction with more traditional methods will allow us to interrogate the pathogenic mechanisms employed by macrophages in this system. Immune complexes, IL-17, and macrophage infiltration are hallmarks of many human autoimmune diseases. We propose to use our novel animal model system to begin to understand how these molecules and cells interact in vivo to provoke tissue pathology, with specific attention to the cardiac valves. The knowledge that we gain is expected to lead to new therapies to reduce the cardiovascular morbidity and mortality among patients with rheumatoid arthritis, lupus, and related autoimmune conditions.